phenethyl isothiocyanate in preventing lung cancer in smokers

Conditions: Lung Cancer; Tobacco Use Disorder

Summary: rationale: chemoprevention is the use of certain drugs to keep cancer from forming. the use of phenethyl isothiocyanate may prevent lung cancer in people who smoke cigarettes. purpose: this randomized clinical trial is studying phenethyl isothiocyanate to see how well it works in preventing lung cancer in smokers.

objectives: primary * to determine whether oral phenethyl isothiocyanate (peitc) affects urinary levels of biomarkers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnk) metabolism in current smokers. secondary * to determine the effect of gstm1 genotype on peitc's impact on urinary biomarkers of nnk metabolism. * to determine the effect of gstm1 genotype on the metabolism and excretion of peitc as measured by urinary levels of its major metabolite. * to determine whether oral peitc affects molecular markers of cell proliferation (ki-67) and apoptosis (caspase-3 and tunel) in bronchial tissue. outline: patients are stratified according to gst genotypes (gstm1 null-null genotype vs gstm1-positive genotype). all participants are initially enrolled in the short-term trial. after the completion of the short-term trial, only those participants meeting certain criteria may proceed to the long-term trial. * short-term trial: participants are randomized to 1 of 2 treatment arms. * arm i: participants are asked to smoke only deuterated nnk cigarettes (provided by the study) and record the exact number of cigarettes smoked and alcoholic drinks consumed each day for 1 month. participants receive oral phenethyl isothiocyanate (peitc) four times daily for 5 days in week 2 and oral placebo four times daily for 5 days in week 4. participants keep a diary of all food and beverages consumed on the days that peitc or placebo are taken. * arm ii: participants receive oral placebo four times daily for 5 days in week 2 and oral peitc four times daily for 5 days in week 4. participants are also asked to smoke only deuterated nnk cigarettes, record the number of cigarettes smoked and alcoholic drinks consumed each day, and keep a food and beverage diary as in arm i. after completion of the short-term trial, participants undergo a wash-out period for 1 month in which they are asked to resume smoking regular cigarettes. participants are offered smoking cessation assistance, if desired. only those participants meeting certain criteria may proceed to the long-term trial after the 1-month wash-out period. * long-term trial: participants are randomized to 1 of 2 treatment arms. * arm i: participants receive oral peitc twice daily for 12 months. * arm ii: participants receive oral placebo twice daily for 12 months. participants in both arms complete a 3-day food diary monthly for 12 months and a food-frequency questionnaire at baseline and at the completion of study treatment. all participants undergo blood and urine sample collection periodically for laboratory studies. participants enrolled in the long-term trial also undergo bronchoscopy and tissue biopsy at baseline and at the completion study treatment. urine samples are examined by liquid chromatography-electrospray ionization-tandem mass spectrometry (lc-esi-ms/ms) for various biomarkers. tissue samples are examined by ihc for ki-67, tunel, and caspase-3 expression.

Eligibility criteria:
inclusion criteria: initial from phone interview: * currently smoking 10-45 cigarettes per day for the past year; * between the ages of 21 and 70 years; * in apparently good physical health with no unstable medical conditions including seizures or cancer; * in stable and good mental health, i.e., currently do not experience unstable or untreated psychiatric diagnosis, including substance abuse, as determined by the dsm-iv criteria, during the past six months; * not using any other tobacco or nicotine-containing products; * not on methadone maintenance or stimulants such as ephedra; not a regular user of street drugs and if uses occasionally, willing to abstain during the study; not taking any drugs known to be p4501a6 substrates such as phenobarbital, rifampicin, dexamethasone, ketoconazole, methoxsalen, pilocarpine, or tranylcypromine due to their role in nnk metabolism; * does not average more than 21 alcoholic drinks per week; * willing to perform study activities such as having blood sample drawn, urine collection, multiple clinic visits; * for female subjects of child bearing potential, not known to be pregnant or nursing, or planning to become pregnant within next 12 months. for enrollment in the short-term trial: * subjects who are generally healthy with liver enzyme and blood count values within the ranges shown below based on blood samples drawn at the second screening visit. specifically: * white blood cells ≥ 3,000/ml * total bilirubin ≤ 1.5 x upper limits of normal (uln) * ast (sgot)/alt (sgpt) ≤ 2.5 x uln * bun and serum creatinine ≤ 1.5 x uln for enrollment in the long-term trial: * participated in the short-term trial and invited to participate in the long-term trial; * possess the gstm1 null-null genotype; * smoke 20 or more cigarettes/day with a cumulative smoking history of 20 or more pack-years (one pack-year equals to smoking a pack of cigarettes a day for one year); * normal liver enzymes based on blood sample drawn during 1 month wash-out; * determined to be a good candidate for the bronchoscopy procedure by a primary care physician. exclusion criteria: * subjects with uncontrolled hypertension, uncontrolled diabetes mellitus, unstable coronary artery disease, history of cancer other than non-melanoma skin cancer, and pregnant or lactating women will not be eligible.

Keywords: non-small cell lung cancer small cell lung cancer tobacco use disorder